Targeting the interleukin-23/17 axis in axial spondyloarthritis

Abstract

Purpose of review: This article highlights and emphasizes how new knowledge of mechanisms linked to the interleukin-23 (IL-23)/IL-17 pathway is relevant to the pathophysiology of axial spondyloarthritis (axSpA) and demonstrates how molecules in IL-23/IL-17 pathway provide novel therapeutic targets for axSpA patients.

Recent findings: Similarly to ankylosing spondylitis (AS), the increased frequency of Th17 cells in nr-axSpA patients underscores the concept that these disorders can be viewed on a spectrum. Recent findings suggest that the contribution of IL-23/IL-17 signaling pathways possibly differs in male and female AS patients. The finding that IL-17 and IL-22 secreting-type 3 innate lymphoid cells are increased in AS patients point to their potential role in the pathogenesis of axSpA. Reports of dysbiosis in the gut microbiome of AS patients support previous work indicating a possible causal relationship between altered gut flora, ileocolonic inflammation and axSpA. Of important clinical relevance are results from clinical trials supporting the efficacy and safety of agents that block IL-12/23 (ustekinumab) and IL-17 (secukinumab and ixekizumab) in AS patients.

Summary: Recent studies further establish the central position of the IL-23/IL-17 pathway in the pathogenesis of axSpA. Targeting the IL-23/IL-17 pathway appears to be a safe and effective strategy for treatment of axSpA patients.

Figure 1. The IL-17/IL-23 pathway in axSpA pathogenesis

The convergence of genetic and epigenetic factors, environmental triggers, mechanical stress, and gut dysbiosis promote an inflammatory response in the gut and joints through activation of dendritic cells, macrophages, synovial fibroblasts and other resident cells. In the resulting inflammatory response, these cells secrete an array of inflammatory cytokines such as IL-1β, IL-6, IL-23 and TGF-β. Elevated levels of IL-1β, IL-6, IL-23 and TGF-β generate Th17 cell differentiation resulting in an increased frequency of IL-17 and IL-22 secreting CD4+ cells along with Th22, CD8⁺IL17+ (Tc17), type 3 innate lymphoid cells (ILC3), NK cells and neutrophils. IL-17 secreted by these cells, together with increased levels of RANKL and TNF-α, leads to increased osteoclastogenesis and bone erosion whereas IL-22 may drive pathologic new bone formation, resulting in altered bone remodeling and radiographic damage in axSpA.

Figure 2. Targeting IL-17/IL-23 pathway with neutralizing agents

IL-23 is a heterodimer of p40 (IL-12p40) and p19 (IL-23p19). Ustekinumab binds to IL-12p40 and blocks the binding of both IL-12 and IL-23 to their receptors. BI655066 binds sIL-23p19 and block the binding of IL-23 to IL-23R. Secukinumab and ixekizumab bind IL-17A and block the binding of both IL-17A and IL-17A/F to their receptor. Bimekizumab and MSB0010841 bind and neutralize both IL-17A and IL-17F isoforms. Brodalumab binds IL-17RA and blocks the binding of IL-17A, IL-17A/F, IL-17F, IL-17C, and IL-17E to their receptors. Fezakinumab binds and neutralizes IL-22.